1. Field of the Invention
The field of the invention includes at least medicine, immunology, cell biology, and molecular biology. In certain aspects the field of the invention includes immunotherapy.
2. Description of Related Art
Allogeneic hematopoietic stem-cell transplantation (HSCT) can cure some patients with high risk B-cell leukemia/lymphoma, but relapse remains a major cause of death. To improve the graft-versus-leukemia/lymphoma (GVL)-effect, donor-derived T cells can be genetically modified to express a tumor-specific chimeric antigen receptor (CAR) with specificity derived, for example, from the variable domains of a monoclonal antibody, thus focusing immunoreactivity towards the tumor in an MHC non-restricted manner (Cooper et al., 2004). However, the endogenous αβ T-cell receptor (TCR) on infused allogeneic T cells may recognize major and minor histocompatibility antigens in the recipient, leading to graft-versus-host-disease (GVHD). As a result, the majority of current clinical trials infuse autologous CAR+ T cells relying on immune tolerance to prevent TCR-mediated deleterious recognition of normal tissues after adoptive transfer (Jena et al., 2010). This approach has achieved early clinical successes (Kochenderfer et al., 2010), but is limited by the time and expense to manufacture patient-specific T-cell products.
CD19 is constitutively expressed on most acute and chronic B-cell malignancies. Therefore, to target malignant B cells, the Sleeping Beauty (SB) transposon/transposase system was adapted for human application, e.g., to stably express a CD19-specific CAR (designated CD19RCD28) (Kohn et al., 2011; Izsvak et al., 2010; Hackett et al., 2010; Williams, 2008; see U.S. Pat. No. 6,489,458, incorporated by reference herein in its entirety). SB modified CAR+ T cells can be numerically expanded to clinically-sufficient numbers by the recursive addition of γ-irradiated designer artificial antigen presenting cells (aAPC) that co-express CD19 and desired T-cell co-stimulatory molecules (Singh et al., 2008; Davies et al., 2010). This has been adapted for clinical translation at M.D. Anderson Cancer Center, as four clinical trials based on the electroporation and propagation of CAR+ T cells have achieved institutional and federal regulatory approvals for the adoptive transfer of CD19RCD28+ T cells after autologous and allogeneic hematopoietic stem-cell transplantation (e.g., IND #14193, ClinicalTrials.gov Identifier: NCT00968760) (Jena et al., 2010; Kohn et al., 2011; Hackett et al., 2010; Williams, 2008). However, a need in the art remains to develop methods and reagents that circumvent the time and expense to manufacture patient-specific T-cell products.